PROJECT SUMMARY: OVERVIEW Teenagers use cannabis more than any other recreational drug. Their developing brains may also be especially vulnerable to its effects, as epidemiological and experimental evidence suggests that frequent cannabis use in adolescence may be associated with impairments in cognitive and affective functioning that continue in adult life. Excessive stimulation of the endogenous cannabinoid (ECB) system ? the target of cannabis?s main psychoactive component, ?9-tetrahydrocannabinol (THC) ? is a plausible but still poorly understood mechanism for the long-lasting consequences of cannabis use. We propose the creation of a NIDA Center of Excellence, entitled Impact of Cannabinoids Across Lifespan (ICAL), to test the hypothesis that non-physiological activation of the ECB system in adolescence ? caused by exposure to THC ? initiates an epigenetically driven reprogramming of the processes that govern the molecular structure, neuroanatomical architecture and synaptic functions of this system, ultimately producing persistent abnormalities in cognition and motivated behavior. To test this hypothesis, ICAL will deploy a vertically integrated strategy combining molecular, neuroanatomical, electrophysiological and behavioral approaches. Specific mechanistic questions will be addressed bringing to bear, as needed, current techniques such as chemogenetic (DREADD) control of neural circuit activity. Synergistic integration within ICAL will be fostered by (a) a shared Administrative Core that will ensure the seamless operation of the center; (b) Animal and Analytical Cores, which will provide a consistent and well-characterized source of experimental subjects for all projects; and (c) a Pilot Core, which will allow for the exploration of important new ideas arising inside or outside the center. A structured set of measures (strict adherence to treatment protocols, animal subject randomization, blind-testing) will ensure the rigor and reproducibility of our studies. A broad program of outreach activities will target the scientific community (through undergraduate/graduate student and faculty mentoring, a bimonthly seminar series and an international ?state-of-the-field? workshop, sponsored by the peer-reviewed journal Cannabis and Cannabinoid Research), health care professionals and general public (through an annual Cannabis Awareness Day and a website dedicated to the lay-term dissemination of new scientific discoveries in the field). In a context of rapidly changing laws, social attitudes and economic interests, the enduring consequences of adolescent cannabis use on brain development and mental function remain largely unknown. ICAL?s mission is to fill this knowledge gap while enhancing our mechanistic understanding of the functions serves by the ECB system in the brain, educating a new generation of cannabinoid researchers, and disseminating scientific discoveries about cannabis and its effects.